The present invention relates to ophthalmic compositions that are delivered to the interior of an eye of a human or animal. More particularly, the invention relates to ophthalmically acceptable compositions including one or more therapeutic agents. Such compositions are advantageously intraocularly placed into the interior of an eye and form solid or semi-solid drug delivery elements in situ that are effective in providing extended or delayed release of the therapeutic agent or agents into the eye.
Steroids, for example corticosteroids, among other agents, are utilized to treat a wide variety of ophthalmic diseases that affect the posterior segment of an eye. Examples of some diseases treated with corticosteroids include: central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), choroidal macular edema (CME), diabetic macular edema (DME), diabetic macular retinopathy, uveitis, telangitis, and age related macular degeneration (ARMD) as well as other diseases or conditions of the eye, for example of the posterior segment of the eye.
In treating ocular diseases or disorders, steroids can be administered systemically. However, systemic administration of steroids is often associated with side effects that are often too substantial for ophthalmic use. Thus, topical, suprachoroidal, subconjunctival, retrobulbar, and intravitreal administration have also been studied. These administration techniques typically employ aqueous compositions containing a steroid.
The desired site of action for therapeutic agents administered to the posterior segment of an eye generally, and corticosteroids in particular, is the retinal pigmented epithelium (RPE). The RPE is a single cell layer responsible for maintenance of the blood-retinal barrier as well as subretinal fluid volume and composition. The cells of the RPE comprise the outer blood retinal barrier and are joined by zonulae occludente tight junctions. As such, permeation of compounds into the RPE is quite limited. Thus, regardless of the administration route, penetration of a therapeutic agent through the outer blood-retinal barrier is limited. To overcome these limitations extremely high and potentially toxic doses of drugs are frequently used.
In certain situations, drugs are administered by controlled or sustained release technologies to attempt to increase their duration of action or reduce the toxicity of transient high general concentrations.
Some poorly soluble therapeutic agents, such as corticosteroids, however, are well tolerated locally and have a prolonged duration of action by virtue of their own intrinsic dissolution rates. For example, triamcinolone acetonide has been successfully administered by direct intravitreal injection in an aqueous composition due to its slow dissolution rate and tolerability. Unfortunately, side effects from the existing triamcinolone acetonide formulation often include endophthalmitis as well as retinal toxicity from the benzyl alcohol preservative. Glaucoma and cataract are also observed.
Reducing the lens concentration of a corticosteroid may help mitigate the cataractogenic potential of these drugs. Additionally, reducing the anterior segment concentration of the corticosteroids relative to the posterior concentrations may reduce the chance of elevating the TIGR (MYOC, GLC1A) gene activity in the trabecular meshwork thought to be associated with steroid induced glaucoma.
Some extended release compositions containing therapeutic agents have been described. For example, U.S. Pat. No. 5,077,049 discloses a biodegradable system for regenerating the periodontium. U.S. Pat. No. 5,324,519 discloses a biodegradable polymer composition. U.S. Pat. Nos. 5,487,897 and 6,395,293 disclose a biodegradable implant precursor. U.S. Pat. No. 5,702,716 discloses polymeric compositions useful as controlled release implants. U.S. Pat. No. 5,717,030 discloses an adjunctive polymer system for use with medical device. U.S. Pat. No. 5,780,044 discloses liquid delivery compositions. U.S. Pat. No. 6,143,314 discloses controlled release liquid delivery compositions with low initial drug burst. U.S. Pat. No. 6,261,583 discloses a moldable solid delivery system. U.S. Pat. No. 6,461,631 discloses a biodegradable polymer composition. U.S. Pat. No. 6,565,874 discloses polymeric delivery formulations of leuprolide with improved efficacy.
Thus, there is a need for new ophthalmic compositions for injection into the interior of eyes of humans or animals and methods for providing desired therapeutic effects of ophthalmic conditions of eyes of humans or animals.